Substituted-3,5-seco-a-nor-pregnan-3-oic-acids

ABSTRACT

This invention is directed to substituted-3,5-seco-A-norpregnan-3-oic-acids and derivatives thereof which are useful as intermediates in the synthesis of known 9 Beta ,10 Alpha steroids of the pregnane series. The latter compounds can be utilized as both progestational and salt-retaining agents.

United States Patent 260/345.3, 345.9, 488 B, 476 C, 485 L, 941,

Uskokovic Sept. 25, 197 3 1 SUBSTITUTED-3,S-SECO-A-NOR-PREGNAN-3-OlC-ACIDS [56] References Cited [75] Inventor: Milan Radoje Uskokovic,Upper UNlTED STATES PATENTS Montclair, N1 3,336,341 8/1967 Fare et 1.260/456 P 1, v 3,198,792 8/1965 Reerink et a1. 260/239.55 [73] Ass1gnee:Hoffmann-La Roche Inc., Nutley. 3,412,107 11/1968 Uskokovic et al.260/3409 NJ. 1 Primary Examiner-Howard T. Mars [22] Ffled' June 1968Assistant ExaminerLeo B DeCrescente I [2]] Appl.' N0.: 736,568 7 vAttorney-Samuel L. Welt, Jon S. Sax'e, Bernard S.

' Related U.S. Application Data Leon and w'lham Epstem [60] Division ofSer. No. 499,094, Oct. 20, 1965, Pat. No.

3,574,761, which is a continuation-in-part of Ser. No. 7 ABSTRACT400,206, Sept 29, 1964, p 3412 107 This 1nvent1on is directed tosubstituted-3,5-seco-A- nor-pregnan-3-oic-acids and derivatives thereofwhich 52 US. Cl 260/456 R, 260/3405, 260/3407, are useful asintermediates in the synthesis of known 2 0/345 3 ,2 0/345 9 2 0/455 C 29/333 9B,10a-steroids of the pregnane. series. The latter corn- 2 0/45 ppounds can be utilized as both progestational and salt- [511 1m. (:1C07d 15/00 retaining agents- [58] Field of Search 260/456 P, 456 R,

5 Claims, No Drawings SUBSTITUTED-3 ,5-SECO-A-NOR-PREGNAN-3- OIC-ACIDSRELATED APPLICATIONS DETAILED DESCRIPTION OF THE INVENTION Thisinvention relates to novel chemical intermediates and processes usefulin the preparation of steroids.

Natural steroids possess a 911,10B-stereochemicalconfiguration.Steroidal compounds possessing the unnatural 913,10a-configurationrepresent a pharmaceutically valuable class of compounds which, eventhough numerous members are known in the art, cannot be obtained bytotally classical chemical means.- In fact, the only known methods forobtaining steroids possessing the unnatural 9B,10a-configuration involveat least one photochemical reaction. Such photochemical reactionsinvolve irradiation with ultraviolet light of strong intensity for longperiods of time and, in comparison with purely chemical reactions, arevery inefficient and give only small yields.

It is an object of the presentinvention to provide intermediates andprocesses which enable the preparation of 93,10a-steroids without thenecessity of proceeding through a photochemical reaction. It is also anobject of this invention to provide novel intermediates and processeswhich will enable the further exploration of steroids having theunnatural 9B,l0a-configuration. It is also an object of this inventionto provide novel 9 B, l Oct-steroids.

The novel intermediates and processes of this invention are valuable andprovide a new synthetic route completely of a classical chemical nature,i.e., involving no photochemical reaction, for converting steroidshaving the normal configuration into steroidal compounds possessing theunnatural 9B,10a-c0nfiguration.

In one aspect, the novel intermediates and processes of this inventionenable the preparation of 913,100:- steroids of the androstane series ofthe formula wherein R is, individually, selected from the groupconsisting of hydroxy and lower alkanoyloxy; R is, individually,hydrogen orlower alkyl and R and R taken together, are. selected fromthe group consisting of 17B-OH, Hal-lower alkanoic acid lactone) and x0;

- R is selected from the group consisting of hydrogen,

2 Other 9B,lOa-androstanes, the preparation of which is enabled by theintermediates and processes of this invention, are of the formulae 1'--lo\vor alkeuyl n n I I X Y II HaC 1 -lower alkynyl 2 H l I Y IIIwherein R,, R Y and X have the same meaning as above. Compounds offormula III are useful as progestational agents and compounds of formulaII are useful as anti-androgenic agents.

In another embodiment of this invention, the novel compounds andintermediates provided by this invention enable the preparation of9B,]Oa-steroids of the l7B-pregnane series of the formula CIIz-Rs HaC 00 wherein R;,, R Y. and X have-the same meaning as above.

Compounds of formula V are useful as salt-retaining agents, i.e., areuseful in the treatment of Addisons disease.

As used herein, the term lower alkyl comprehends both straight andbranched chain saturated hydrocarbon groups, such as methyl, ethyl,propyl, isopropyl and the like. Similarly, the term lower alkanoylcomprehends groups such as acetyl and the like, and the term loweralkanoyloxy comprehends groups e.g., formyloxy acetoxy and the like. Inthe same manner, the term lower alkenyl comprehends groups such as vinyland the like, and the term lower alkynyl comprehends groups such asethinyl and the like. Halogen comprehends all four halogens, i.e.,iodine, bromine, chlorine and fluorine.

The expression l7B-OI-I, 17a-lower alkanoic acid lactone) refers to aconfiguration on the C-l7 carbon atom illustrated as follows:

wherein W is lower alkylene, e.g., polymethylenes such as ethylene,propylene or the like.

With respect to substituents in the 6- and 7-position, preferredcompounds are those having hydrogen or lower alkyl in 6- or 7-position,and those having halogen in the 7-position.

In one aspect, this invention comprises a method for the preparation of9B, a-androstanes of formulae I-III and of 9B,]Oa-l7B-pregnanes offormulae IV-V which comprises the hydrogenation of desA-androst-9-en-5-ones or of desA-l7,8-pregn-9-en-5-ones to 9B,l0/3-desA-androstan-S-ones or 9B, 1 OB-desA- l 7B-pregnan- 5-ones,respectively, followed by condensation with a lower alkyl vinyl ketonewith methyl or ethyl vinyl ketone preferred (as well as substitutestherefor such as l-tertiary amino-3-butanone, l-tertiary amino-3-pentanone and quaternary ammonium salts thereof), l-Q-butan-3-one,l-Q-butan-3-one lower alkylene ketal, l-Q-butan-B-ol, esterifiedl-Q-butan-3-ol, l-Q- butan-3-ol ether, 1,3-di-chlorobut-2-ene, 1,3-dichloropent-Z-ene. l-pentan-3-one, l-Q-pentan-3-one lower alkyleneketal, l-Q-pentan-3-ol, esterified l-Q- pentan-3-ol or l-Q-pentan-S-olether, which condensation yields the desired 9B,l0asteroids. The symbolQ is bromine, chlorine or iodine, with the former two being preferred.This invention also provides a number of different methods for thepreparation of said desA- androst-9-en-5-one ordesA-l7B-pregn-9-en-5-one starting materials from natural steroids.

In one embodiment, a steroid f the 3-oxo-androst- 4-ene or3-oxo-I7B-pregn-4-ene series is subjected to an oxidative ring openingof the A-ring yielding a 5- oxo-3,S-seco-A-norandrostan-3-oic acid or a5-oxo- 3,5-seco-A-nor-17B-pregnan-3-oic acid, which 3-oic acid can thenbe converted to a mixture of a IOa-desA- androstan-S-one and aIOB-desA-androstan-S-one or a mixture of a IOa-desA-l7B-pregnan-5-oneand a IOB-desA-l7B-pregnan-5-one. The conversion of the 3-oic acid tothe desA-compound can be effected ei ther by pyrolysis of a salt of said3-oic acid or via the enol lactone, i.e., a 4-oxoandrost-5-en-3-one or a4-oxo-17B-pregn-5-en- 3-one, which upon reaction with a Grignard reagentgives an aldol, which in turn can be converted into the desireddesA-compound.

The desA-compound can then be converted into the starting materialdesA-androst-9-en-5-one or desA-l7B-pregn-9-en-5-one via a two-stepsequence of halogenation and dehydrohalogenation.

In another embodiment of this invention, desA- androst-9-en-5-one ordesA-l7B-pregn-9-en-5-one starting materials can be prepared fromll-hydroxy steriods of the 3-oxo-androst-4ene or 3-oxol 7,8-pregn- 4-eneseries. This can be effected in a variety of ways. In one approach, anll-hydroxy group of a steriod of the 3-oxo-androst-4-eneor3-oxo-l7B-pregn-4-ene series is converted into a leaving group, forexample, a sulfonic acid ester or carboxylic acid ester. Oxidative ringopening of the A-ring of the thus formed 11- (esterifiedhydroxy)-containing compound yields the corresponding 1 l-(esterifiedhydroxy)-5-oxo-3,5-seco- A-norandrostan-3-oic acid or 1 l-(esterifiedhydroxy)- 5-oxo-3,5-seco-A-nor-l7,8-pregnan-3-oic acid which uponpyrolysis of a salt of said 3-oic acid yields the desired'desA-androst-9-en-5-one or desA-l7B-pregn-9- en-5-one startingmaterial.

A further approach involves formation of an 11-hydroxy-desA-androstan-S-one or ll-hydroxy-desA- l7B-pregnan-5-one froman I l-hydroxy steriod of the 3-oxo-androst-4-ene or3-oxo-17/3-pregn-4-ene series via an oxidative ring opening of theA-ring of said 1 1- hydroxy steroid which yields an ll-hydroxy-S-oxo-A-nor-3,5-seco-androstan-3-oic acid 3,1l-lactone or an 11-hydroxy-5-oxo-3,5-secol 7B-pregnan-3-oic acid 3,11-lactone which, inturn is converted into a salt of the corresponding keto acid which saltupon pyrolysis gives the 11-hydroxy-desA-androstan-5-one or 1lhydroxy-desA-l7B-pregnan-5-one. Esterification of the l l-hydroxymoiety of the so-obtained compound with an acid moiety yields an 1l-(esterified hydroxy)-desA- androstan-S-one or an ll-(esterifiedhydroxy)-desA- l7B-pregnan-5-one which upon elimination of the leavinggroup (i.e., the esterified hydroxy moiety) gives the desireddesA-androst-9-en-5-one or desA-l7B-pregn- 9-en-5-one starting material.Though, in the above reaction sequence either 1 la-OH or 1 lB-Ohstarting material steriods can be used, it is preferred to usel la-OHstarting materials.

As will be appreciated from the above discussion, neither the specificreaction steps nor the reaction sequences of this invention involve anymodification of substituents found in the l6-and/or l7-position of thestarting material natural steriods. However, in order to obtainunnatural 9B,lOa-steroids of formulae I-V, it is necessary or desirableto protect certain of the 16- and/or l7-substituents against one or moreof the reaction steps involved. It is also convenient to initiallyprotect such a substituent in the starting material natural steriod andmaintain the substituent in its protected form throughout the entirereaction sequence, regenerating the desired substituent only when thesteroid of formulae I-V possessing the unnatural 98,1011- configurationis obtained. On the other hand, it is sometimes convenient to insert aprotecting group only before a certain reaction step or sequence ofreaction steps. Said protecting group can then be maintained until thefinal reaction step or can be split off at some intermediate stage. Theprotecting groups can be inserted and split off by means known per se.The desirability of having protecting groups present will be furtherdiscussed below when specific reaction steps are discussed in detail.The various substituents which are susceptible to being protected areexemplified by the l6-hydroxy group in a compound of any of formulasl-V, the l7B-hydroxy group in a compound of any of formulas l--lll, thel 7a-hydroxy or -oxo group in a compound of any of formulas lV-V, the2l-hydroxy group of a compound of formula V or the l7-oxo group of acompound of formula l.

The l7-oxo or 20-oxo group is suitably protected by ketalization, i.e.,by reaction with a lower alkanediol, to yield a l7-lower alkylene dioxyor 20-lower alkylene dioxy compound, i.e., a l'i-ketal or a ZO-ketal.

The l-hydroxy, l7a-hydroxy, l7fl-hydroxy or 21- hydroxy moieties can beprotected by esterification and/or etherification of the hydroxy group.Any available acid which will form an ester that can subsemethyl etherssuch as, for example, the benzyl, benzv hydryl and trityl ethers, ora-lower alkoxy-lower alkyl ethers, for example, the methoxymethyl, orallylic ethers.

In compounds containing the dihydroxyacetone side chain at C-l7 (forexample, compounds of formula V wherein R is hydroxy), the side chain at(3-17 can be protected by forming the 17,20; 20,2l-bismethylenedioxygroup or by forming a l7,2l-acetal or ketal group, or by forming al7,2l-diester. The l7,2lacetal or ketal and l7,2l-diester hinder theZO-ketone group and minimize the possibility of its participating inunwanted side reactions. On the other hand, the l7,-20;20,2l-bis-methylenedioxy derivatives actually convert the ketone to anon-reactive derivative. When both a l6a-hydroxy and l7a-hydroxysubstituent are present, these groups can be protected via formation ofa l6a,l 7a-acetal or ketal. The various protecting groups mentionedabove can be-removed by means known per se, for example, by mild acidhydrolysis.

In compounds wherein there is present neither a 170:- hydroxy nor 2 1-hydroxy substituent but there is present a 20-oxo group, the 20-oxogroup can be protected via reduction to the corresponding carbinol(hydroxy) group. Thus, for example, the l7-acetyl side chain can beprotected via conversion to a l7-(oz-hydroxyethyl)- side chain.Regeneration of the l7-acetyl side chain can be simply effected viaconventional oxidation means, for example, via oxidation with chromiumtrioxide in an organic solvent such as glacial acetic acid. Similarly incompounds containing a l7-oxo, this group can be protected by reductionto the corrresponding carbinol (hydroxy) group. Thus, the l7-oxo groupcan be reduced to a l7B-OH, l7oz-H moiety, from which, when desired, thel7-oxo moiety can be regenerated by oxidation, as described above.Furthermore, a 20- hydroxy or 17,8-hydroxy group, can itself beprotected by esterifcation, for example, with a lower alkanoic acid suchas acetic acid, caproic acid, or the like; or by etherification withmoieties such as tetrahydropyranyl,

benzyl, benzhydryl, trityl, allyl, or the like.

The 1601-1701 or 1701,21-acetals and ketals above discussed can beformed by reacting l6oz,l7oz-bis-hydroxy or 17o1,2l-bis-hydroxy startingmaterials with an aldehyde or a ketone; preferably it is done byreacting a simple acetal or ketal (i.e., a lower alkylene glycol acetalor ketal of a suitable aldehyde or ketone) with the moieties sought tobe protected.

Suitable aldehydes and ketones include lower alkanals of at leasttwocarbon atoms, such as paraldehyde, propanal and hexanal; di(loweralkyl)ketones, such as acetone, diethylketone, dibutylketone,methylethylketone, and methylisobutylketone; cycloalkanones, such ascyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (loweralkanals), such as cyclopentylcarboxaldehyde andcyclohexylcarboxyaldehyde; cycloalkyl lower alkyl ketones, such ascyclopentyl propyl ketone, cyclohexylmethyl ethyl ketone; dicycioalkylketones, such as dicyclopentyl ketone, dicyclohexyl ketone andcyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones,such as cyclohexyl pchlorophenyl ketone, cyclopentyl o-methoxyphenylketone, cyclopentyl, o,p-dihydroxy-phenyl ketone and cyclohexyl m-tolylketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such ascyclopentylmethyl phenyl ketone; cycloallcyl monocyclic aromatic-loweralkyl ketones, such as cyclopentyl benzyl ketone and cyclohexylphenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkylketones, such as cyclopentylmethyl benzyl ketone; halo-lower alkanals,such as chloral hydrate, trifluoroacetaldehyde hemiacetal, andheptafluorobutanal ethyl hemiacetal; halolower allcanones, such as1,1,l-trifiuoroacetone; mono cyclic carbocyclic aromatic aldehydes, suchas benzaldehyde, halobenzaldehydes (e.g., pchlorobenzaldehyde andp-fluorobenzaldehyde), lower alkoxy-benzaldehydes (e.g.,o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g., veratraldehyde),hydroxybenzaldehydes (e.g., salicyl-aldehyde), lower alkyl benzaldehydes(e.g., m-tolualdehyde and pethylbenzaldehyde), di(loweralkyl)-benzaldehydes (e.g., o-p-dimethylbenzaldehyde); monocycliccarboxylic aromatic lower alkanals, such as phenylacetaldehyde,a-phenylpropionaldehyde, B-phenylpropionaldehyde, 4-phenylbutyraldehyde,and aromatically-substituted halo, lower alkoxy, hydroxy and lower alkylcyano derivatives thereof; monocyclic carbocyclic aromatic ketones, suchas acetophenone, a,a,a-trifluoroacetophenone, propiophenone,butyrophenone, valerophenone, halophenyl lower alkyl ketones (e.g.,p-chloroacetophenone and pchloropropiophenone); (lower alkoxy) phenyllower alkyl ketones (e.g., p-anisyl methyl ketone); di-(lower alkoxy)phenyl lower alkyl ketones; hydroxy-phenyl lower alkyl ketones; (loweralkyl)phenyl lower alkyl ketones (e.g., methyl p-tolyl ketone); di(loweralkyl) phenyl lower alkyl ketones (o,p-xylyl methyl ketone;benzophenone, and mono-or bis-substituted halo,

lower allcoxy, hydroxy and lower alkyl derivatives thereof; monocycliccarbocyclic aromatic lower alkanones, such as l-phenyl-S-butanone andl-phenyl-4- pentanone, and aromatically substituted derivatives thereof.

Especially suitable are those aldehydes or ketones which, with the1601,1701- or :,2l-bis-hydroxy grouping form an acetal or ketal group ofthe formula wherein P is individually selected from the group consistingof hydrogen and lower alkyl; Q is individually selected from the groupconsisting of lower alkyl and aryl; and P and Q taken together are loweralkylene. The term lower alkylene comprehends polymethylene chains suchas tetramethylene and pentamethylene.

In discussing the various starting materials, intermediates andend-products of this invention, the various protecting groups discussedabove will not necessarily be specifically mentioned, but it should beunderstood that mention of any substituent comprehends the variousprotected forms thereof, unless specifically mentioned to the contrary.

In one embodiment of this invention, compounds of formula I through Vare prepared from 9B,l0B-desA- androstan-S-ones or93,10B-desA-pregnan--ones of the formula ANVRQ VII wherein R R R and Xhave the same meaning as above.

Similarly 9B,]Oa-androstanes of formula II can be prepared from9fi,lOB-desA-androstan-S-ones of formula VIII and 9B,l0a-androstanes offormula III from 9B,IOB-desA-androstan-S-ones of formula IX.

---lo\ver alkenyl VIII l ---lower alkynyl \MNR3 H l l 8 wherein R R andX have the same meaning as above. Moreover, 9B,l0a-l7B-pregnanes offormulae IV and V can be prepared from 9,8,lOB-desA-pregnan-S-ones offormulae X and XI, respectively.

wherein R' R R and X have the same meaning as above.

The conversion of a 9B,10B-desA-compound of formula VI to a9B,l0a-steroid of formula I-V (i.e., VII I, VIII ll, IX III, X IV and XIV) is effected by condensing the 9B,1OB-desA-compound with a compoundselected from the groupconsisting of lower alkyl vinyl ketone (as wellas substitutes therefor such as l-tertiary amino-3-butanone, l-tertiaryamino-3- pentanone and quaternary ammonium salts thereof),l,3-dichlorobut-2-ene, 1,3-dichloropent-2-ene, l-Q- butan-3-one,l-Q-butan-3-one lower alkylene ketal, l- Q-butan-B-ol, l-Q-butan-3-olether, esterified l-Q- butan-3-ol, l-Q-pentan-3-one, l-Q-pentan-3-onelower alkylene ketal, l-Q-pentan-3-ol, l Q-pentan-3-ol ether oresterified l-Q-pentan-3-ol. Q is bromo, chloro or iodo, with the formertwo being preferred. Methyl vinyl ketone and l-tertiary amino-3-butanoneare the preferred reagents, and the former is especially preferred.Prior to the condensation it is desirable to protect the 20-keto grouppresent in compounds of formulae X and XI, then it is not necessary toprotect l6a,l7a or 2l-hydroxy groups which are present, but groupsprotecting these moieties can be retained through the condensationreaction.

The above indicated substitutes for lower alkyl vinyl ketones arecompounds wherein the vinyl moiety is replaced by a moiety of theformula wherein each R is lower alkyl or taken together both R's arelower alkylene, oxa-lower alkylene or aza-lower alkylene. Such moietiesare, for example, dimethylamino, diethylamino, pyrrolidino, piperidino,morpholino, or the like. The quaternary ammonium salts thereof areformed via the utilization of conventional quaternizing agents, forexample, lower alkyl or phenyl-lower alkyl (especially benzyl) halides,mesylates or tosylates.

When a lower alkyl 'vinyl ketone or substitute therefor, l-Q-butan-3-oneor l-Q-pentan-3-one is used as the reaction partner for thecondensation, ring closure to ring A (containing a 3-oxo moiety) of thedesired 9B,]Oa-steroid of formulae l-V occurs simultaneously with thecondensation. However, when 1,3- dichlorobut-Z-ene,l,3-dichloropent-2-ene, l-Q-butan- 3-one lower alkylene ketal,l-Q-butan-3-ol, l-Qbutan- 3-ol ether, esterified l-Q-butan-3-ol,l-Q-pentan-B-one lower alkylene ketal, l-Q-pentan-3-ol, l-Q-pental-3-olether, or esterified l-Q-pentan-3-ol is used as the reaction partner asubsequent step to generate the 3-oxo moiety is required. When1-Q-butan-3-ol or 1-0- pentan-3-ol is used as the reaction partner, thex0 moiety can be generated by oxidation and for this purpose, it issuitable to use oxidation means known per se, for example, chromic acid,chromium trioxide in acetic acid or the like. When esterified oretherified l-Q- butan-3-ol or esterified or etherified l-Q-pentan-S-olis used as the reaction partner, hydrolysis of the esterified via theuse of an aqueous mineral acid such as hydrochloric 'acid, sulfuric acidor the like. When a 1-0- butan-3-one lower alkylene ketal or al-Q-pentan 3-one lower alkylene ketal is used as the reaction partner,mild acid hydrolysis of the ketal moiety results in generation of the3-oxo moiety. Finally, when 1,2- dichlorobut-3-ene or1,3-dichloropent-3-ene is used as the reaction partner, the 3-oxo moietycan be generated by treatment with a concentrated mineral acid,preferably a strong acid such as hydrochloric acid or sulfuric acid. Itshould be noted, that 1,3-dichlorobut- 2-ene and 1,3-dichloropent-2-enemay be used as reaction partners with compounds of formulae X and XI,but not with the l7a-lower alkyl, alkenyl or alkynyl compounds offormulae Vlll-lX.'As will be apparent, when a reaction partner based onbutane (i.e., having a four carbon atom skeleton) is utilzed a compoundof formulae l-V wherein Y is hydrogen is obtained. Similarly, when areaction partner based on pentane is utilized a compound of formulae l-Vwherein Y is methyl is obtained.

In addition to the preparation of compounds of formulae I.-V fromcompounds of formulae VI-Xl by the use of the above mentioned reactionpartners, it is also possible by the procedures of this invention toprepare compounds of formulae I-V which, in the A-ring, in addition tocontaining an unsaturation between the 4- and 5-positions also containan unsaturation between the 1- and 2-positions. Such 1,4-diene productscorresponding to the compounds of formulae I-V can be prepared fromcompounds of formulae VI-Xl by condensation of the latter with areaction partner selected from the group consisting of ethinyl methylketone and ethinyl ethyl ketone (as well as substitutes therefor such asB-tertiary amino-vinyl methyl or ethyl ketone, quaternary ammonium saltsthereof, and B-lower alkoxy-vinyl methyl or ethyl ketone). Condensationto prepare such a l,4-diene product corresponding to the compounds offormulae l-V is effected under the same conditions as is thecondensation to prepare a compound of for- 5 mulae l-V. The so-obtained1.4-dienes are useful in the same way as the correspondingly substituted4-enecompounds of formulae l-V.

The condensation is suitably effected at, below or above roomtemperature. For example, at the reflux temperature of the reactionmedium or at ice temperature (0 C.) or below. Moreover, the condensationis suitably effected in an organic medium. Preferably the solvent is alower alkanol, such as methanol, isopropanol, tert-butanol, ethanol, oranother non-ketonic or- 5 ganic solvent, such as an ether, e.g.,dioxane, diethyl ether, diisopropyl ether, aromatic hydrocarbon, e.g.,benzene, toluene, xylene, organic acid, such as acetic acid, or thelike. Lower alkanols are the preferred solvents. It is suitable tocatalyze the condensation, and this can be efiected via use of acatalyst such as an alkali metal lower alkoxide, for example sodiumethoxide, potassium t-butoxide, sodium t-amylate, or the like, alkalimetal hydroxide such as sodium, lithium or potassium hydroxide, aquaternary ammonium hydroxide, for example, a benzyl tri-lower alkylammonium hydroxide such as benzyl trimethyl ammonium hydroxide,para-toluene sulfonic acid, or the like.

When using a substitute for methyl or ethyl vinyl ketone, or for methylor ethyl ethinyl ketone, the condensation should be effected underalkaline conditions. As indicated above, among such substitutes arel-tertiary amino-3-butanone, 1tertia'ry amino-3-pentanone and B-tertiaryamino-vinyl methyl or ethyl ketone. Pregroups such as dimethylamino,diethylamino, pyrinc MR3 11 I l llaC k X XII l[3C llh I 'l0wcra.kenylI136 Iii X XIII ferred tertiary amino groups are dilower alkylaminowherein R R R and X have the same meaning as above. Also,9B,IOB-desA-pregnan-S-ones of formulae X and XI can be prepared byhydrogenation of desA- pregn-9-en-5-ones of the formulae X IV m {I inc fwherein R' R R and X have the same meaning as above.

Prior to hydrogenation, the C- keto group in compounds of formulae XVand XVI or C-l7 keto group in compounds of formula XIII should beprotected either by conversion to the corresponding carbino or byketalization as described above. The hydrogenation can, however, beeffected without protecting such keto groups.

Moreover, it should be noted that the hydrogenation, besides inserting ahydrogen atom in each of the 9- and l0-positions, can alsosimultaneously effect hydrogenation of other groups in the molecule. Forexample, the C-20-keto group can be hydrogenated to the correspondingcarbinol or the C17 lower alkenyl group in compounds of formula XIII orthe G17 lower alkynyl group in compounds of formula XIV can behydrogenated to the corresponding C-l7-lower alkyl compounds. Compoundsof formulae VIII and IX can, in turn, be prepared from compounds offormula VII wherein R, and R together are oxo via reaction with a loweralkenyl or lower alkynyl Grignard reagent, with prior protection of theS-keto group, for example, by forming S-ketals without concurrentblocking of the l7-keto group. In the same manner compounds of for- 6 Itis particularly advantageous to use rhodium, for example, rhodium oncharcoal (or carbon powder, carbon black, or the like) or rhodium onalumina. In contrast to what would be expected, it has been found thatsuch a catalytic hydrogenation of a compound of formulae XII-XVI gives asubstantial yield ofa compound of formulae VI-XI. In fact, it has beenfound that such catalytic hydrogenation gives a major proportion of acompound of the formulae VI-XI. This catalytic hydrogenation is suitablyeffected in an inert organic solvent, for example, a lower alkanol suchas methanol or ethanol, an ether such as dioxane or diglyme, ahydrocarbon such as cyclohexane, hexane, or the like. Lower alkanols arepreferred solvents. Moreover, it is suitably conducted in the presenceof an acidic or basic catalyst, for example, an alkali metal or alkalineearth metal hydroxide such as sodium hydroxide or the like, or a mineralacid, for example, a hydrohalic acid, such as hydrochloric acid, or thelike, or an organic acid such as a lower alkanoic acid, for example,acetic acid. The reaction can be conducted at, above or below roomtemperature, for example, from about 5 C. to about C. However, it ispreferably conducted at a temperature between about 0 C. and about 35 C.

As described above, the desA-androst-9-ene-5-ones ordesA-l7B-pregn-9-en-5-ones of formulae XII-XVI can be prepared fromnatural steroids by a variety of methods. Thus, in one embodiment ofthis invention said desA-androst-9-en-5-ones or desA-l7B-pregn-9-en-5-ones can be prepared from steroids of the 3-oxoandrost-4-ene or3-oxo-l7B-pregn-4-ene series by a reaction sequence which involves as afirst step an oxidative ring opening of ring A of the natural steroid.For this oxidative ring opening there can be used as starting materials,natural steroids of the 3-oxo-androst-4-ene or 3-oxo-17B-pregn-4-eneseries of the formula:

XVII

wherein X is a substituent in the 6-position selected from the groupconsisting of hydrogen, lower alkyl, lower alkylthio and loweralkanoylthio or a substituent in the 7-position selected from the groupconsisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthioand halogen, and Z represents the carbon and hydrogen atoms necessary tocomplete the steroid D- ring, as well as the atoms in the substituentsin the 16- and 17-positions as defined in formulae 1, IV, and V above.The oxidative ring opening of a natural steroid of formula XVII yields a5-oxo-3,5-seco-A-norandrostan-3-oic acid or a5-oxo-3,5-seco-A-norpregnan-3-oic 0 acid of the formula XVIII wherein Xand Z have the same meaning as above. The oxidative ring opening of thecompound of formula XVII can be performed by a variety of methods. In apreferred embodiment it is effected by ozonolysis. The ozonolysis issuitably carried out in an organic solvent, for example, acetic acid,ethyl acetate, methanol, chloroform, methylene chloride, or the like, ora mixture of two or more of such solvents such as ethyl acetate/a- 1cetic acid, ethyl acetate/methylene chloride, or the like. Moreover, theozonolysis is advantageously'conducted at below room temperature. Thus,it is preferably conducted at a temperature between about 70 C. andabout 25 C..The resulting ozonides can be decomposed by conventionalmeans, for example, by treatment with water, hydrogen peroxide in water,acetic acid or ethyl acetate, or the like. The oxidative ring opening ofa compound of formula XVII to a compound of formula XVIII can also beeffected by other oxidation means, for example, by treatment withhydrogen peroxide. It should be noted than an oxidative ring opening byeither ozonolysis or by treatment with hydrogen peroxide, does notrequire protection of any of the substituents at C-l6 or C-l'l. However,as stated above, it may be desirable to protect these substituentsagainst some subsequent reaction in the total reaction sequence beingpracticed. On the other hand, the oxidative ring opening can also beeffected by oxidation with chromium trioxide or via treatment withsodium periodat'e and potassium permanganate in potassium carbonatesolution and if these oxidation means are used, it is necessary toprotect any secondary hydroxy groups which might be present such as a16,17B- or 21- hydroxy group; preferably, for the purpose of thisreaction, with non-aromatic protecting groups.

Following the oxidative ring opening of the A-ring, the so-obtained-oxo-3,5-seco-A-norandrostan-3-oic acid or5-oxo-3,5-seco-A-norpregnan-3-oic acid of formula XVIII is convertedinto a mixture of a IOa-desA- androstan-S-one and aIOB-desA-androstan-S-one or a mixture of a lOa-desArpregnan-5-one and aIOB-desA- pregnan-S-one as illustrated below:

XVIII alkali metal salt-oi XVIII rolysis. In effecting the pyrolysis, itis desirable to convert the 3-oic acid of formula XVIII into acorresponding metal salt, for example, an alkali metal salt such as thesodium or lithium salt. This conversion to a metal salt can be effectedprior to pyrolysis, e.g., by treating the acid with sodium hydroxide orin situ during the course of the pyrolysis, e.g., by fusing the 3-oicacid with a mixture of sodium acetate and potassium acetate. Thepyrolysis can be conducted at atmospheric pressure or in a vacuum. Onepreferable embodiment is to conduct the pyrolysis in a vacuum, at atemperature from about 200 C. to about 350 C. in the presence of aproton acceptor, e.g., an alkali metal or alkaline earth metal salt of-aweak organic acid, for example, potassium acetate, sodium acetate,sodium phenylacetate, sodium bicarbonate, or the like; especiallypreferred is a vacuum of from about 0.001 to about 0.5 mm. Hg.Accordingly, it is advantageous to conduct the pyrolysis under alkalineconditions, i.e., at a pH greater than 7. The pyrolysis can be effectedin solution or by fusion. An especially preferred method of effectingthe pyrolysis is by fusion of an alkali metal salt of a weak acid, forexample, an organic carboxylic acid such as a lower alkanoic acid or aphenyl-lower alkanoic acid such as phenyl-acetic acid. Another method ofeffecting the pyrolysis is to heat, preferably at atmospheric pressure,a solution of an alkali metal salt, such as the sodium or lithium salt,of a 3-oic acid of formula XVIII in a basic organic solvent. The basicorganic solvent should, of course, be one which is in the liquid stateat the temperature at which the pyrolysis is effected. Thus, thepyrolysis can be effected at a temperature up to the boiling point ofthe basic organic solvent being used. Suitable basic organic solventsare, for example, nitrogen containing organic solvents such aspiperidine, pyridine, isoquinoline, quinoline, triethanolamine, or thelike. When utilizing this approach using a basic organic solvent it issuitable to heat to temperature between about 200 C. and about 300 C.,and preferably between about 230 C. and about 260 C. A preferred basicorganic solvent for the pyrolysis of a salt of a compound of formulaXVIII to compounds of formulae XIX and XX is quinoline. If a basicorganic solvent is used which boils substantially below 200 C. at atmospheric pressure, it is suitable to conduct the pyrolysis in a sealedtube or an autoclave.

In another aspect, compounds of formula XIX can be prepared fromcompounds of the formula by ozonolysis as described above for theconversion of a compound of formula XVII to a compound of formula XVIII.Such ozonolysis of a compound of formula XIX A yields a compound of theformula llsc XIX B wherein X and Z have the same meaning as above, and Ais carboxy or formyl. A compound of formula XIX B can then be convertedto a compound of formula XIX. This removal of the residue of the A-ring,i.e., decarboxylation and deformylation, can be effected by heating inan acidic or basic medium. It is preferred to heat to the refluxtemperature of the medium which is preferably an inert organic solventsuch as a lower alkanol, e.g. ethanol, dioxane, ether or the like. Thedecarboxylation and deformylation yields mainly a compound of formulaXIX, but also a minor yield of the corresponding lOB-isomer of formulaXX.

Compounds of formula XIX can also be formed from a compound of formulaXVIII via the formation of an enol-lactone of a compound of formulaXVIII, i.e., via the formation of a 4-oxo-androst-5-en-3-one or a4-oxo-pregn-5-en-3-one of the formula:

l l f H X XXI wherein X and Z have the same meaning as above, which canthen be reacted with a Grignard reagent, such as phenyl magnesiumbromide or phenyl lithium, to form the resulting aldol of, for example,the formula wherein X and Z have the same meaning as above, which, upontreatment with an alkali metal hydroxide, such as potassium hydroxide,at an elevated temperature, for example, from about 200 C. to about 240C., is converted to the corresponding lOa-desA-androstan- 5-one orIOa-desA-pregnan-S-one of formula XIX.

It should be noted that though the pyrolysis of a compound of formulaXVIII yields both the 103- compounds of formula XX'and the IOa-compoundsof formula XIX, and though either of these isomers can be used in thesubsequent halogenation and dehydrohalogenation steps of this reactionsequence, it is sometimes preferable to convert the lOB-compound offormula XX into the corresponding IOa-compound of formula XIX. Thisconversion can be effected by treating OII XXII alOB-desA-androstan-S-one or IOB-desA-pregnan- 5-one of formula XX withany base capable of producing a curb-anion; for example, it is suitableto use an alkali metal lower alkoxide in an organic solvent such as alower alkanol, for example. sodium cthoxide in an ethanol solution orsodium methoxide in a methanol solution.

The above-discussed conversion via the alkali metal salt and pyrolysisof compounds of formula XVIII to compounds of formulas XIX and XX can beeffected without protection of any of the substituents which might bepresent at C-l6 or C-l7. However, if it is desired for either precedingor succeeding reaction steps of the total reaction sequence, theconversion of a compound of formula XVIII to compounds of formulas XIXand XX can be effected with protecting groups present on substituents inthe C-l6 or C-17 position.

As stated above, the IOa-desA-androstan-S-ones orlOa-desA-pregnan-S-ones of formula XIX or the 103- desA-androstan-S-onesof IOB-desA-pregnan-S-ones of formula XX can be converted via a two-stepsequence of halogenation and dehydrohalogenation into the desiredstarting material desA-androst-9-en-5-one or desA-pregn-9-en-5-one offormulas XII, XV, and XVI.

In a preferred embodiment a lOa-desA-androstan- 5-one or alOa-desA-pregnan-S-one of formula XIX is subjected to the two-stepsequence of halogenation and dehydrohalogenation. I-Ialogenation of acompound of formula XIX or a compound of formula XX yields a mixture ofcorresponding halogenated compounds including one of the formula XXIIIwherein X and Z have the same meaning as above, and Hal is a halogenatom (preferably Br or Cl). Dehydrohalogenation of a compound of formulaXXIII then yields a desired starting material of formulas XII, XV andXVI. Keto groups except for the S-keto group, may require protectionprior to the halogenation. In the case of compounds of formulas XIX andXX containing the C-17 dihydroxyacetone side chain, represented informula V wherein R is hydroxy, this protection can be effected byformation of the l7a,20;20,2l-bismethylenedioxy derivative. In othercases wherein a C-l7 oxo or C-20 oxo group is present, protection can beeffected by reduction to the corresponding carbinol either directlyprior to the halogenation step or prior to some other step in thereaction sequence leading to the compounds of formulas XIX and XX.

The halogenation can be effected with halogenating agents such asbromine, sulfuryl chloride, or the like. Bromination is especiallypreferred. The bromination is suitably effected by treatment withbromine at room temperature or below, preferably at ice temperature orbelow. Suitably it is conducted in an organic medium; for example, anorganic acid such as acetic acid; an ether such as an anhydrous ether,dioxane, tetrahydrofuran; a chlorinated organic solvent such asmethylene chloride, chloroform, carbon tetrachloride; or the like; withthe addition of hydrogen bromide as a catalyst.

When effecting halogenation with sulfuryl chloride, it

is suitable to use the same type of organic medium as when brominating;and suitable catalysts are, for example, acetic acid, benzoyl peroxide,or the like.

The subsequent dehydrohalogenation of a compound of formula XXIII'ispreferably conducted under mild dehydrohalogenating conditions; forexample, by the use of an alkali metal carbonate (e.g., lithiumcarbonate) or an alkali metal halogenide (e.g., a lithium ha lide) in anorganic solvent such as a di-lower alkylformamide, or with an organicbase such as collidine, pyridine, or the like. The dehydrohalogenationis advantageously conducted at slightly elevated temperatures, forexample, from about 50 C. to about 150 C., preferably about 80 C. toabout 120 C.

Separation of the desired product'desA-androst-Q- en-S-one ordesA-pregn-9-en-5-one of formulas XII, XV and XVI can be effected byconventional means. As indicated above the halogenation procedure mayresult in halogenated by-products in addition to the desiredintermediate of formula XXIII. Accordingly, the separation is preferablyeffected after first subjecting the reaction mixture to dehalogenatingconditions in order to dehalogenate the halogenated by-products formedby the halogenation procedure, but not dehalogenated by thedehydrohalogenation. Following such dehalogenation the reaction mixturecan then easily be separated by conventional means, for example, bycolumn chromatography, to yield the desired compound of formulas XII,XV, XVI. An examplary dehalogenation means is treatment with zinc andsodium acetate in an acetic acid solution at an elevated temperature,for example, about 80 C.

In the case of compounds of formulas XIX or XX which contain a halogenatom on a carbon atom directly adjacent to a keto group, it ispreferable to protect such a halogen atom against dehalogenation priorto subjecting thecompoundof formulas XIX or XX to the two step sequenceof halogenation and dehydrohalogenation of this embodiment. Such agrouping, containing a halogen atom on a carbon atom directly adjacentto a keto group, is illustrated in a compound of formulas IV or Vwherein R or R is halogen. Thus, if 1001- or IOB-desA-pregnan-S-one offormulas XIX or XX containing a 1701- or 2l-halo substituent is to besubjected to the halogenation-dehydrohalogenation sequence it isdesirable to first effect protection of the 17aor 2l-halo substituent.This protection can be effected, for example, by ketalization of the20-oxo XXIV wherein X and Z have the same meaning as above, is reactedwith an acid or a reactive derivative thereof to form a leaving group inthe l l-position. By reactive derivative is meant, for example, ahalide, e.g. a chloride,

an anhydride, or the like. Though either 1 1B- or 1 lahydroxy startingmaterials can be used, it is preferable 5 to utilize a-hydroxy compoundsof formula XXIV as starting materials. Prior to the esterificationreaction, it is preferable to protect hydroxy groups present in theC-l6, C-l7, or 021 position. Suitable acids for the esterification ofthe l l-hydroxy group, which can be used to form a leaving group in thel l position are inorganic acids such as phosphoric acid, organiccarboxylic acids such as anthraquinone B-carboxylic acid or organicsulfonic acids, for example, toluene-sulfonic acids, especiallyp-toluene sulfonic acid, lower alkyl-sulfonic acids such asmethanesulfonic acid and nitrophenyl-sulfonic acids, especiallyp-nitrophenylsulfonic acid. Especially preferred as the leaving group inthe ll-position is a lower alkylsulfonyloxy group such as the mesoxygroup. However, when it is desired to react a compound of formula XXIVwith a sulfonyloxy forming moiety, then a compound of formula XXIVhaving an 1 lot-configuration should be used as a starting material. Theabove described esterification of l I-hydroxy steroid starting materialsof formula XXIV yields compounds of the formula II THU XXV XXVI

wherein X, Z and LO have the same meaning as above particularly acompound, in accordance with this invention, having the formula:

0 XXVI-A wherein R is individually selected from the group consisting ofhydrogen, fluoro, lower alkyl, hydroxy, lower alkanoyloxy,carboxyloweralkanoyloxy and benzoyloxy; R is individually selected fromthe group consisting of hydrogen, halogen, hydroxy, lower alkanoyloxy,carboxyloweralkanoyloxy and benzoyloxy; R is individually selected fromthe group consisting of hydrogen, lower alkyl, halogen, hydroxy,loweralkanoyloxy, carboxyloweralkanoyloxy and benzoyloxy; X is asubstituent in the 6- or 7-position selected from the group consistingof hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio andhalogen; L is selected from the group consisting of toluene sulfonate,lower alkyl sulfonate, and nitrophenyl sulfonate; R is individuallyhydroxy, loweralkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy,tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy orlower alkoxy lower alkoxy; and R is individually hydrogen or, takentogether with R oxo or lower alkylenedioxy; or R and R taken togetherform a ketal or acetal of a lower alkanal containing at least two carbonatoms, a di(loweralkyl)ketone, a cycloalkanone containing from four tosix carbon atoms, a (cycloalkyl containing five or six carbon atoms)lower alkanal, a (cycloalkyl containing five or six carbon atoms) loweralkanone, a dicycloalkyl ketone containing from II to 13 carbon atoms, aphenyl lower alkanone, or benzophenone; or R R and R taken together forma bismethylenedioxy; or R and R taken together form a ketal or acetal ofa lower alkanal containing at least two carbon atoms, adi(loweralkyl)ketone, a cycloalkanone containing from four to six carbonatoms, a (cycloalkyl containing 5 or 6 carbon atoms) lower alkanal, a(cycloalkyl containing five or six carbon atoms) lower alkanone, adicycloalkyl ketone containing from 1 1 to 13 carbon atoms, a phenyllower alkanone, or benzophenone..

The oxidative ring opening of the A-ring of a compound of formula XXV toa compound of formula XXVI can be effected by ozonolysis as describedabove for the oxidative ring opening of the A-ring of a comppound offormula XVII to a compound of formula XVIII. Pyrolysis of the so-formedcompound of formula XXVI under the conditions described above for thepyrolysis of a compound of formula XVIII to compounds of the formulasXIX and XX directly yields the desired desA-androst-9-en-5-one ordesA-pregn-9-en-5-one of formulas XII, XV, XVI. Thus, pyrolysis ofacompound of formula XXVI directly results in elimination of the leavinggroup in the l l-position as well as a splitting off of the residue ofring A attached to the lO-position. This procedure of starting from an 1l-hydroxy steroid (preferably lla-hydroxy) of formula XXIV andproceeding through intermediates of formulas XXV and XXVI to compoundsof formulas XII, XV, XVI, represents a particularly elegant procedurefor preparing the latter compounds. An especially preferred method ofeffecting the pyrolysis of a salt of a 3-oic acid of formula XXVI is themethod described above wherein the salt of the 3-oic acid is heated in aliquid base organic solvent. Especially preferred solvents for thepyrolysis of a salt of a compound of formula XXVI are triethanolamineand quinoline.

As indicated in the foregoing paragraph the pyrolysis of a salt of acompound of formula XXVI involves two separate chemical attacks; onebeing the elimination of the ll-leaving group and the other being thesplitting off of the A-ring residue. Instead of effecting these twoXXVI-A wherein X and Z have the same meaning as above. The eliminationcan be efiected by any conventional elimination means. It is suitablyconducted under alkaline conditions in an anhydrous organic solvent.Preferably, it is effected by heating, i.e., at a temperature betweenabout room temperature and the reflux temperature of the reactionmixture. Thus, treatment of a compound of formula XXVI with either aninorganic or organic acid or base results in the formation of thedesired compound of formula XXVIA. Preferably a weak base is used, forexample, a salt of a carboxylic acid (e.g., a lower alkanoic acid) withan alkali metal or an alkaline earth metal, for example, sodium acetate,potassium acetate, or the like. As indicated, the elimination issuitably conducted in an anhydrous organic solvent; suitable aresolvents such as dilower alkylformamides, e.g., dimethylformamide, loweralkanoic acids, e.g., acetic acid, or the like. When a proton acceptingsolvent, such as dimethylformamide, is used, it itself can serve as thebase for the purpose of this elimination reaction; i.e., if the solventis basic then the elimination can be conducted without the addition of aseparate basic material. Similarly, if the solvent is acidic, then theelimination can be conducted without the addition of a separate acidicmaterial.

After the elimination is effected the A -seco acid product of formulaXXVIA can then be converted to a salt, for example, an alkali metalsalt, and the soforrned salt pyrolyzed according to the conditionsdescribed above for the pyrolysis of a compound of formula XXVI tocompounds of formulas XII, XV and XVI.

After the above-described l l-leaving group elimination and A-ringresidue splitting, conducted either simultaneously or sequentially, thedesired desA-9-en- S-one compounds of formulas XII, XV and XVI can beisolated by conventional means. However, it has been found particularlysuitable with compounds of formulas XV and XVI to isolate by forming thedisemicarbazone of the pyrolysis product and then regenerating therefromthe desired 5,20-dione of formulas XV or XVI, or if the 20-oxo group hasbeen protected, for example, by reduction to a ZO-hydroxy moiety, byforming the semicarbazone at the 5-position and then regeneratingtherefrom the desired 5-one compound.

In yet another embodiment of this invention starting material 1l-hydroxy steroids of formula XXIV can be directly subjected to anoxidative ring opening of the A-ring by ozonolysis or treatment withhydroxide peroxide, as described above for the oxidative ring opening ofthe A-ring of a compound of formula XVII to a compound of formula XVIII.This oxidative ring opening of the A-ring of a compound of formula XXIVyields an ll-hydroxy-5-oxo-3,S-seco-A-norandrostanall I o H XXVII alkalimetal salt wherein in formulas XXVIII and XXIX, X and Z have the samemeaning as above. This pyrolysis of an alkali metal salt derived from acompound of formula XXVII can be effected under the same conditions asdescribed above for the pyrolysis of a compound of formula XVIII tocompounds of the formulae XIX and XX. Though either the IOB-compound offormula XXVIII or the loot-compound of formula XXIX can be subjected tothe subsequent steps of this reaction sequence, it is suitable toutilize the IOB-compound of formula XXVIII. Conversion of thelOa-compound of formula XXIX to the lOB-compound of formula XXVIII canbe effected under the same conditions as described above for theconversion of the compound of formula XX to a compound of formula XIX.

In the next step of this reaction sequence, the 11- hydroxy compound offormula XXVIII or of formula XXIX can be subjected to esterificationwhereby to convert the ll-hydroxy group to a leaving group in the 1l-position. This esterification can be effected with the 1 same acids oracid derivatives and in the same manner as described above for theesterification of a compound of formula XXIV to a compound of formulaXXV. As in that instance, it is also preferred in the present instanceto form a mesoxy leaving group in the l 1- position, though, of course,other leaving groups as described above are useful for the instantpurpose. There is thus obtained a compound-of the formula XXX wherein X,Z and LO have the same meanings as above. The leaving group can then beeliminated from the l l-position of a compound of formula XXX resultingin a direct formation of a desA-androst-9-en-5-one or adesA-pregn-9-en-5-one of formulae XII, XV, XVI. This elimination can beeffected by any conventional elimination means. It is suitably conductedunder alkaline conditions in an anhydrous organic solvent. Preferably,it is effected by heating, i.e., at a temperature between about roomtemperature and the reflux temperature of the reaction mixture. Thus,treatment of a compound of formula XXX with either an inorganic ororganic base results in the formation of the desired compound offormulae XII, XV, XVI. Preferably a weak base is used, for example, asalt of a carboxylic acid (e.g., a lower alkanoic acid) with an alkalimetal or an alkaline earth metal, for example, sodium acetate, potassiumacetate, or the like. As indicated, the elimination is suitablyconducted in an anhydrous organic solvent; suitable are solvents such asdilower alkylformamides, e.g., dimethyl formamide, lower alkanoic acids,e.g., acetic acid, or the like. When a proton accepting solvent, such asdimethyl formamide, is used, it itself can serve as the base for thepurpose of this elimination reaction; i.e., if the solvent is basic thenthe elimination can be conducted without the addition of a separatebasic material.

In another aspect, compounds of Formula XXX can be prepared fromcompounds of the formula XXXA wherein X, Z and LO have the same meaningsas above. The compounds of formula XXXA can be prepared fromcorresponding ll-hydroxy compounds by esterification as described abovefor the preparation of compounds of formula XXV from compounds of formula XXIV. The compounds of formula XXX can be prepared from compoundsof formula XXXA in the same manner that compounds of formula XXX are prepared from compounds of formula XXV, i.e., by oxidative ring opening ofthe A-ring of a compound of formula XXXA followed by elimination of theresidue of the A-ring to yield a compound of formula XXX. The oxidativering opening of the compounds of formula XXXA can be performed byozonolysis as described above for conversion of a compound of formulaXXV to a compound of formula XXVI. Such ozonolysis of a compound offormula XXXA yields a compound of the formula XXXB wherein X, Z and LOhave the same meaning as above. A compound of formula XXXB can then beconverted to a compound of formula XXX. This removal of the residue ofthe A-ring, i.e., decarboxylation, can be effected as described abovefor the conversion of a compound of formula XIXB to a compound offormula XIX.

The compounds of formulae I-V preparable by the methods of thisinvention are not only pharmaceutically useful compounds as describedabove, but also are themselves useful as intermediates for other9B,l0a-steroids; for example, compounds wherein X is hydrogen or loweralkyl can be modified so as to introduce unsaturation between C-6 andC-7. This can be effected by dehydrogenation means, for example, byhalogenation followed by dehydrohalogenation or by means of2,3-dichloro-5,6-dicyanobenzoquinone, according to known methods. Thus,for example, a

9B,10a-progesterone of formula IV wherein X is by drogen or lower alkylcan be converted to a 98,100:- pregna-4,6-dien-3,20-dione.

A further embodiment of this invention comprises the preparation of9B,l0a-steroids of formulae I-V containing an ll-hydroxy substituent.This can be effected by utilizing an 1 1-hydroxy-lOa-desA-androstan--one or ll-hydroxy-IOa-desA-pregnan-S-one of formula XXIX or anll-hydroxy-b l0BdesA-androstan- S-one orll-hydroxy-IOB-desA-pregnan-S-one of formula XXVIII as the startingmaterials. It is preferred in this embodiment to use the IOB-isomers offormula XXVIII as starting materials. As a first step in this the ll-hydroxy group of the compound of formulae XXVIII or XXIX should beprotected. This is suitably effected by esterification, preferably witha carboxylic acid, for example, a lower alkanoic acid such as aceticacid, benzoic acid, or the like. Conversion of the soobtainedll-esterified hydroxy compound then yields an ll-(esterifiedhydroxy)-desA-androst-9-en-5-one (i.e., a compound of formula XIIcontaining an 11- esterified hydroxy moiety). or an ll-esterifiedhydroxy-desA-pregn-9-en-5-one (i.e., a compound of formulae XV-XVIcontaining an lla-esterified hydroxy moiety). This conversion can beeffected by halogenation followed by dehydrohalogenation, as describedabove for the conversion of a compound of formulae XIX or XX to acompound of formulae XII, XV or XVI. Catalytic hydrogenation of theso-obtained compound of the formula XXXI wherein X and Z have the samemeaning as above, and E0 is an esterified hydroxy group as describedabove in this paragraph, yields an I l-esterfied hydroxy-desA-9/3l0B-androstan-5-one or 1 l-esterfied hydroxy-desA-9,8,10/3-pregnan-5-one, of the formula XXXII wherein X, Z and E0 havethe same meaning as above.

This compound can be conducted in the same manner as described above forthe hydrogenation of a compound of formulae XII-XVI to a compound offormulae VII, X, XI. Also, compounds of formula XXXII containing al7-oxo moiety can be converted to a corresponding compound containing al7B-hydroxy, 17alower alkenyl or lower alkynyl moiety by the methodsdescribed above. Also, compounds of formula XXXII can be hydrolyzed toyield corresponding ll-hydroxy compounds of formula XXXII, i.e., whereinE0 is hydroxy.

Condensation of the so-obtained compound of formula XXXII or thecorresponding l7B-hydroxy, 17alower alkenyl or lower alkynyl compound(i.e., a compound of formula VI containing a free or 1 l-esterifiedhydroxy group) then yields the desired end-product 9B, IOa-steroid offormulae I-V containing an I l-hydroxy group. Such condensation can beeffected as described above for the preparation of a compound offormulae I-V from a compound of formulae VIXI. The soobtained9B,l0a-steroids containing an ll-esterified hydroxy group can behydrolyzed to the corresponding compounds containing an I l-hydroxygroup, which latter compounds are themselves useful as intermediates,for example, the l l-hydroxy group can be oxidized by methods known perse to yield corresponding ll-oxo steroids analogous to compounds offormulas I-V.

The pharmaceutically useful compounds prepared by the methods of thisinvention can be administered internally, for example, orally orparenterally, with dosage adjusted to individual requirements. They canbe administered in conventional pharmaceutical forms, e.g., capsules,tablets, suspensions, solutions, or the like.

The following examples are illustrative but not limitative of thisinvention. All temperatures are in degrees Centigrade. The Florisilabsorbent used infra is a synthetic magnesia-silica gel available fromthe Floridin Company, P. O. Box 989, Tallahassee, Fla. (cf. p. 1590,Merck Index, 7th Edition, 1960). -200 mesh material was used. The moietydesignated by tetrahydropyranyloxy is tetrahydro-Z-pyranyloxy. When itis stated that a procedure is effected in the cold, it should beunderstood that is is commenced at 0 C. Throughout this application whencompounds of the pregnane series are referred to it should be understoodthat it is LOM- MR3 compounds of the I'IB-pregnane series that are beingreferred to, unless specifically indicated to the contrary, and whetheror not the compound of the pregnane series is specifically indicated asof the l7B-series.

EXAMPLE 1 A solution of 3.2 g. of l7a-ethyltestosterone in 50 ml."

methylene chloride and 25 ml. 'ethyl acetate was ozon-' ized at 70(acetone-dry ice bath) until the solution was blue in color. Afteroxygen was passed through, the solution was evaporated at roomtemperature in vacuo. The syrupy residue was then dissolved in 100 m1.ofglacial acetic acid, and after addition of 5 ml. of 30 per centhydrogen peroxide, left for 24 hours at -5. Following this time, it wasevaporated to dryness, dissolved in 1500 ml. ether, and extracted with2N sodium carbonate solution. The alkaline extract was poured in icecold hydrochloric acid. The resultant crystalline l7-a-ethyl-17,8-hydroxy--oxo-3 ,5-seco-Amorandrostan- 3-oic acid wasfiltered, washed with water and dried. Upon being recrystallized fromacetone, it melted at l- 96-197"-.

EXAMPLE 2 A solution of 1.5 g. of l7d-ethyl-17B-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid in 100 ml. of methanol was titratedwith 2N sodium methoxide to the reddish color of phenolphthaleine, andthen evaporated to dryness in vacuo, giving as the residue, the sodiumsalt of l7a-ethyll 7B-hydroxy-5-oxo-3,5-seco-A-norandros tan-3-oic acid.5 g. of sodium-phenylacetate was added to the residue, and the mixturepyrolyzed in vacuo 0.1 mm) at 285-295, for 2.5 hours. The sublimate wasdissolved in acetone, filtered and the filtrate concentrated in vacuo.The resultant syrupy residue was chromatographed on a 60 g. Florisil(adsorbent) column. The fractions eluted with benzene and 0.5 per centethylacetate in benzene were combined and gave l7a-ethyll 7B-hydroxylOa-desA-androstan-S-one, m.p. 94-95 after recrystallization frompetroleum ether. The fractions eluted with 2 per cent and 5 per centethylacetate in benzene were combined and gave 1 7a-ethyl-l7B-hydroxy-1OB-desA-androstan-S-one, m.p. 185l 855, after tworecrystallizations from petroleum ether.

EXAMPLE 2a:

To a solution of 100 mg. of l7a-ethyl-l7B-hydroxy-IOB-desA-androstan-S-one in 10 ml. of absolute ethanol was added oneequivalent of sodium ethoxide dissolved in 5 ml. of absolute ethanol.This reaction mixture was maintained at room temperature overnight,

then acidified with glacial acetic acid, poured in water i of anhydrousether), arid after cooling in a salt-ice bath, several drops of 30 percent hydrobromic acid in acetic acid were added. This was followed bythe dropwise addition during five minutes of 0.684 g. of brominedissolved in 2 ml. of acetic acid. This addition was synchronized withthe decoloration rate of the reaction mixture. Immediately after this, 5ml. of a saturated solution of sodium bisulfite and 5 ml. of 2N sodiumcarbonate solution were added. The mixture was then transferred into aseparatory funnel, 500 ml. of ether added, shaken and separated. Theether part was washed with water, dried and evaporated. The resultantbromides were dissolved in 100 ml. of dimethylformamide, and afteraddition of 3 g. of lithium carbonate, the solution was heated at 100for 45 minutes. After cooling, it was poured into one liter of ether,washed with water, 1N hydrochloric acid, 2N sodium carbonate, water,dried and evaporated. The residue was dissolved in 40 ml. of glacialacetic acid, 1.2 g. of sodium acetate and 1.2 g. of zinc powder added,and the soformed mixture heated 10 minutes at It was then poured intoone liter' of ethylacetate and the resultant solution washed withsaturated sodium bicarbonate, then with water, dried and evaporated. Theresidue was chromatographed on Florisil (adsorbent) column. The fractionwith benzene and one-half per cent ethylacetate in benzene gaveregenerated starting material. Fractions with 1 and 2 per centethylacetate in benzene gave l7a-ethyll7/3-hydroxy-desA-androst-9-en-5-one, which after sublimation (140 and0.1 mm. Hg vacuum), was obtainedv as a glass. [111 -36.6' (c=1, CHClEXAMPLE4 A suspension of 262 mg. of 5 per cent rhodium on aluminacatalyst in a mixture of 26 ml. of per cent ethanol and 5.25 ml. of 2Nsodium hydroxide solution was pre-reduced, (i.e., hydrogenated at roomtemperature and atmospheric pressure). To this was added a solution of262 mg. of 17a-ethyl-17fihydroxy-desA- androst-9-en-5-one in 15 ml. of95 per cent ethanol, and the mixture then hydrogenated at atmosphericpressure and room temperature. After one moleequivalent of hydrogen wasabsorbed, the reaction was stopped, the catalyst was separated byfiltration, and the filtrate evaporated in vacuo. Glacial acetic acid 1ml.) was added to the residue, which was then dissolved in 1 liter ofether. The cloudy solution which resulted was washed with 2N Na COsolution, then with water, dried and evaporated to dryness in vacuo.

The reaction was repeated 3 more times, and the combined productschromatographed on a Florisil (adsorbent) column. The eluates with 1 percent ethyl acetate in benzene gave first crystalline fractions, whichwere followed by non-crystalline fractions. The noncrystalline fractionswere dissolved in ml. of methylene chloride, and after the addition of2.5 ml. of 2 per cent cro in 90 per cent acetic acid, stirred overnight.The excess of chromic acid was removed by washing the methylene chloridesolution with 10 ml. of 10 per cent sodium hydrogen sulfite solution,followed by washing with 2N Na CO solution and then with water. It wasthen dried and evaporated in vacuo. The residue was dissolved in 50 ml.of anhydrous ethanol containing 172 mg. of sodium ethoxide, and leftovernight. The next day, after addition of 0.5 ml. of glacial aceticacid, the solution was evaporated in vacuo, and the residue was taken upin 1 liter of ether. The ether solution was washed with 2N Na COsolution, then with water,

dried and evaporated. The residue was chromatographed on Florisil(adsorbent) column and gave crystalline l7a-ethyl-l7B-hydroxy-desA-9B,10B- androstan--one identical (by thinlayer chromatography) with the crystalline material obtained in thefirst chromatographic separation. After two recrystallizations fromether, it melted at l42-l44; [01],, -l 1 .65 [methanol, c=l.245 percent].

EXAMPLE 5 To a solution of 132 mg. ofl7a-ethyl-l7B-hydroxydesA-9BB-androstan-5-one in 12.5 ml. of absoluteethanol containing 34 mg. of sodium ethoxide, 0.15 ml. of

freshly distilled methylvinyl ketone was added. The reaction mixture wasthen refluxed for 2 hours in a nitrogen atmosphere. After cooling thereaction mixture, 0.1 ml. of glacial acetic acid was added thereto andthe resulting mixture was then poured into 1 liter of ether. Theresultant ether solution was washed with water, dried over anhydroussodium sulfate and evaporated in vacuo. The residue was chromatographedon fluorescent silica-gel plates, with the solvent system, 60 per centethyl acetate-40 per cent heptane. The fluorescent part of the layerswas extracted with ethyl acetate. The residue obtained after evaporationof ethyl acetate was first crystallized from ether-petroleum ether, thena second time from pure ether, yielding l7a-ethyl- 9/3,lOa-testosterone,m.p. l31-l35.

EXAMPLE 6 A solution of 6.4 g. of lla-hydroxy-progesterone in 100 ml. ofethylacetate and 50 ml. of methylene chloride was treated with ozone at70 until the solution became blue in color. Oxygen was then passedthrough and the solution evaporated at room temperature in vacuo. Theso-obtained syrupy residue was dissolved in 100 ml. of glacial aceticacid, and after the addition of 5 ml. of 30 per cent hydrogen peroxide,left for 24 hours at 2 (in an ice box). The solution was then evaporatedin vacuo, and the residue triturated with ether yielding crystals.Recrystallization from acetone yielded1la-hydroxy-3,5-seco-A-nor-pregnane-5,20- dione-3-oic acid 3,1l-lactone,m.p. 253-256. [a],, -"+l93.3 (c=l, in chloroform).

EXAMPLE 7 A methanolic solution of 7.5 g. of l 1a-hydroxy-3,5-seco-A-nor-pregnane-S,20-dione-3-oic acid 3,11- lactone was treated withone equivalent of ION sodium hydroxide solution and then evaporated todryness. Sodium phenylacetate (26 g.) was added to the soobtained sodiumsalt and the mixture pyrolyzed at 295 for 2 hours in vacuo. The crudesublimate was chromatographed on a silica-gel column and eluted with 10per cent ethylacetate in benzene. The amorphous solidlla-hydroxy-lOa-desA-pregnane-S,20-dione was first eluted from thecolumn. lR-spectrum in chloroform: 3620 and 3600 cm (OH); 1706 cm(carbonyl group). NMR-spectrum in deuterochloroform: a doublet forloot-CH at 73.5 and 80.5 c.p.s. downfield from TMS at 60 Mc/sec. Furtherelution of the column with 10 per cent ethylacetate in benzene yieldedcrystalline l loz-hydroxy- 1 OB-desA-pregnane-S,20-dione which wasrecrystallized from methylene chloride-petroleum ether, m.p. l50-l52;[01],, 84.0 (c=0.5 in absolute ethanol).

EXAMPLE 8 To a solution of 100 mg. of methanesulfonylchloride in 0.7 ml.of pyridine, there was added 100 mg. of 11ahydroxy-1OB-desApregnane-5,20-dione. The mixture was then allowed tostand overnight at 2 (in a refrigerator), then was diluted with water(100 ml.) and extracted with chloroform (3 X 150 ml.) and methylenechloride (100 ml.). The combined organic extracts were washed withwater, 1N hydrochloric acid and again with water, then dried overanhydrous sodium sulfate and evaporated in vacuo. The crystallineresidue was recrystallized from ether, giving 1la-hydroxylOB-desA-pregnane-S,20-dione methanesulfonate, m.p. 139-l40;[a] +46 (c=0.5 in absolute ethanol).

EXAMPLE 9 A solution of 200 mg. of l la-hydroxy-IOB-desA-pregnane-5,20-dione methanesulfonate in 50 ml. of dimethylformamide wasrefluxed for eight hours and then evaporated to dryness. The residue waschromatographed on a Florisil (adsorbent) column. Elution with 2 percent ethylacetate/benzene and evaporation of the eluant yieldeddesA-pregn-9-ene-5,20-dione in the form of colorless needles, m.p. 1 ll-1 13. It was shown by mixed melting point to be identical with asample of the same compound prepared as described in Example 12.

EXAMPLE 10 To a solution of 20 g. of lla-hydroxy-progesterone in 150 ml.of pyridine maintained at 0, there was added 6 ml. ofmethanesulfonylchloride, and the reaction mixture allowed to standovernight at 0. It was then diluted with a large excess of water andextracted with chloroform. The organic extracts were washed with 2Nhydrochloric acid and water, then dried over anhydrous sodium sulfateand evaporated in vacuo. The solid residue was recrystallized frommethanol to give 1la-mesyloxy progesterone, m.p. l59-160; [011 +1456(c=l, chloroform).

EXAMPLE 1 l A solution of 12 g. of 1la-mesyloxy-progesterone in 300 ml.of methylene chloridelethyl acetate (2:1) was treated with ozone atuntil the solution became blue in color. The excess of ozone was removedby bubbling oxygen through the reaction mixture for 5 minutes. Methylenechloride was then removed under reduced pressure, and the solutiondiluted with ethyl acetate to 200 ml. After addition of 12 ml. of 30 percent aqueous hydrogen peroxide, the reaction mixture was then allowed tostand overnight at 2 (i.e., in the refrigerator), then evaporated to avolume of ml. and diluted with ml. of benzene. The aqueous solution,

obtained by extraction with 8 portions of 75 ml. 2N sodium carbonatefollowed by combining the aqueous extracts was acidified with coldconcentrated hydrochloric acid to pH 2 and extracted with methylenechloride. This extract was dried over anhydrous sodium sulfate andevaporated in vacuo to dryness. The residue crystallized when trituratedwith ether-acetone mixture, yielding crudella-mesoxy-5,20-dioxo-3,5-seco-A- nor-pregnan-3-oic acid. Afterrecrystallization from acetone-petroleum ether, m.p. 152l53; [ct],; 47.9(c 1, chloroform).

EXAMPLE 12 A solution of 6 g. of l la-mesoxy-S,20-dioxo-3,5-seco-A-nor-pregnan-3-oic acid in 150 ml. of methanol was mixed with asolution of 1.5 g. of sodium carbonate in 55 ml. of water. The mixturewas then transferred into a 1 liter sublimation flask, and evaporated todryness. To the thus formed sodium salt, 20 g. of sodium phenyl acetateis added, and after closing the top part of the apparatus, this mixturewas pyrolyzed at 290 and 0.02 mm. for 4 hours. The product, whichcollects on the cold finger, was dissolved in ether and filtered. Thefiltrate was then evaporated to dryness. Purification of the residue bychromatography on a 40 g. silicagel column (benzene eluant) gavecrystalline desA- pregn-9-ene-5,20-dione; m.p. lll-l13 (afterrecrystallization from ether). [11],, 568 0.25 per cent in methanol).

EXAMPLE 13 To a solution of 1.2 g. of desA-pregn-9-ene-5,20- dione in 20ml. of methanol maintained at 0, there was slowly added a cooledsolution of 1.2 g. of sodium borohydride in 22 ml. methanol, and theresultant mixture was left for 72 hours'at 0. It was then diluted with100 ml. of water and extracted with four 100 ml. portions of chloroform.The extract was dried over anhydrous sodium sulfate and evaporated invacuo, yielding a colorless oily product. This product was dissolved in250 ml. of chloroform and 6 g. of manganese dioxide was added to thesolution which was then stirred for 72 hours at room temperature,filtered and the filtrate evaporated to dryness in vacuo. The residuewas chromatographed on a silica-gel column'and the eluates with per centethyl acetate in benzene, after concentration gave crystalline20,8-hydroxy-desA-pregn-9-en- 5-one which upon recrystallization frommethylene chloride-petroleum ether formed colorless needles, m.p.l22-l23; [a 1 33 (c 0.5, absolute ethanol).

EXAMPLE 14 A suspension of 262 mg. of 5 per cent rhodium on aluminacatalyst in a mixture of 26 ml. of 95 per cent ethanol and 5.25 ml. of2N aqueous sodium hydroxide was hydrogenated at room temperature andatmospheric pressure. To this was added a solution of 262 mg. of2OB-hydroxy-desA-pregn-9-en-5-one in 15 ml. of 95 per cent ethanol, andthe reaction mixture then hydrogenated at room temperature andatmospheric pressure. After 1 mole equivalent of hydrogen was absorbed,the reaction was stopped, and the catalyst was separated by filtration.After standing overnight the filtrate was concentrated in vacuo. To theresidue was added 1 ml. of glacial acetic acid,-and it was thendissolved in 1 liter of ether. The cloudy solution was washed with 2Naqueous sodium carbonate solution, then with water, then dried overanhydrous sodium sulfate and evaporated to dryness in vacuo. It yieldeda colorless oil, which was chromatographed on a silicagel column using 1per cent ethyl acetate in benzene as the elutant. First eluted was20,8-hydroxy-l0a-desA- pregnan-S-one, m.p. 107-l08 afterrecrystallization from methylene chloride/petroleum ether. R.D. (inmethanol); [011 25.3, --[oz]. -89; [011 274; 1305 7 3 laoo"" Furtherelution yielded 20B-hydroxy-9B,lOB-desA- pregnan-S-one as a colorlessoil. R. D. (in methanol): [011 l4.8; [121 4.4; [011 22.2"; [041 2l48.

EXAMPLE 15 A suspension of 262 mg. of 5 per cent rhodium on alumina.catalyst in a mixture of 2 ml. of 3N aqueous hydrochloric acid and 18ml. 95 per cent ethanol was hydrogenated at room temperature andatmospheric pressure. A solution of 262 mg. of ZOB-hydroxy-desA-pregn-9-en-5-one in 5 ml. of absolute ethanol was introduced into thehydrogenation flask, and the reaction mixture was then hydrogenated atroom temperature and atmospheric pressure. After one mole-equivalent ofhydrogen was absorbed, the reaction was stopped, the catalyst wasseparated by filtration, and the filtrate neutralized with 2N aqueoussodium hydroxide solution. An excess of 5 ml. of 2N aqueous sodiumhydroxide was added and the solution allowed to stand overnight. Ethanolwas then removed by evaporation at reduced pressure, and after additionof 1 ml. of glacial acetic acid, it was extracted with 1 liter of ether.The

extract was washed with 2N aqueous sodium carbonate solution, then withwater, dried and concentrated in vacuo. It gave a colorless oil, whichwas chromatographed on a silica-gel column using 2 per cent ethylacetate in benzene as the elutant. The first fractions of theeluateyielded, upon concentration, ZOB-hydroxylOa-desA-pregnan-S-one.From the immediately subsequent fraction,20B-hydroxy-9fi,IOB-desA-pregnan- S-one was obtained. Both products wereidentical with the same compounds obtained in Example 14.

EXAMPLE l6 2OB-Hydroxy-9B,l0a-pregn-4-en-3-one is prepared bycondensation of 20B-hydroxy-9B,lOB-desA- pregnan-S-one with methyl vinylketone according to the procedure of Example 5. The product melts atl76.5-l78.5; [a] l43 (chloroform).

EXAMPLE 1 7 A medium is prepared of 20 g. of Edamine enzymatic digest oflactalbumin, 3 g. of corn steep liquor and 50 g. of technical dextrosediluted to 1 liter with tap water and adjusted to a pH of 4.3 4.5.Twelve liters of this sterilized medium is inoculated with Rhizopusnigricans minus strain (A.T.C.C. 6227b) and incubated for 24 hours at 28using a rate of aeration and stirring such that the oxygen uptake is 6.37 millimoles per hour per liter of Na SO according to the method ofCooper et al, Ind. Eng. Chem., 36, 504 1944). To this medium containinga 24 hour growth of Rhizopus nigricans minus strain, 6 g. ofl7a-acetoxy-progesterone in ml. of acetone is added. The resultantsuspension of the steroid in the culture is incubated under the sameconditions of temperature and aeration for an additional 24 hour periodafter which the beer and mycelium are extracted. The mycelium is thenfiltered, washed twice, each time with a volume of acetone approximatelyequal in volume to the mycelium, extracted twice, each time with avolume of methylene chloride approximately equal to the volume of themycelium. The acetone and methylene chloride extracts including solventare then added to the beer filtrate. The mixed extracts and beerfiltrate are then extracted successively with 2 portions of methylenechloride, each portion being one-half the volume of the mixed extractsand beer filtrate, and then with 2 portions of methylene chloride, eachportion being one-fourth the volume of the mixed extracts and beerfiltrate. The combined methylene chloride extracts are then washed with2 portions of a 2 per cent aqueous solution of sodium bicarbonate, eachportion being one-tenth the volume of the combined methylene chlorideextracts. The methylene chloride extracts are then dried with about 3 5g. of anhydrous sodium sulfate per liter of solvent, and then filtered.The solvent is then removed from the filtrate by distillation, and theresidue is dissolved in a minimum of methylene chloride, filtered andthe solvent evaporated from the filtrate. The resulting crystals arethen dried and washed five times, each time with a 5 ml. portion ofether per gram of crystal. The crystals are then recrystallized fromether giving l7a-acetoxyl la-hydroxy-progesterone. l7a-acetoxy-lla-mesoxyprogesterone is prepared by treatment of l7a-acetoxylla-hydroxy-progesterone with methanesulfonyl chloride, according to theprocedure of Example 10.

EXAMPLE l8 l7a-Acetoxy-5,20-dioxo-l la-mesoxy-A-nor-3,5-seco-pregnan-B-oic acid is prepared by ozonolysis of l7a-acetoxy-lla-mesoxy-progesterone, according to the procedure of Example 11.

EXAMPLE l9 l7a-Acetoxy-desA-pregn-9-ene-5,20-dione is prepared froml7a-acetoxy-5,20-dioxo-l la-mesoxy-A- nor-3,5-secopregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 12.

EXAMPLE l7a-Acetoxy-ZOB-hydr0xy-desA-pregn-9-en-5-one is prepared from17a-acetoxy-desA-pregn-9-en-5,20- dione by reduction and reoxidat ionaccording to the procedure of Example 13.

EXAMPLE 21 l 7a-Acetoxy-20B-hydroxy-9/3, 1 OB-desA-pregnan- 5-one isprepared from l7a-acetoxy-20B-hydroxydesA-pregn-9-en-5-one byhydrogenation under acidic conditions in the presence of a rhodiumcatalyst, according to the procedure of Example 15.

EXAMPLE 22 l 7a-Acetoxy-20B-hydroxy-9B,lOa-pregn-4-en-3-one is preparedby condensing methyl vinyl ketone with 17-a-acetoxy-20B-hydroxy-9B,IOB-desA-pregnan-S-one according to theprocecure of Example 5 except instead of conducting the condensation inabsolute ethanol and catalyzing it with sodium ethoxide, thecondensation is conducted in acetic acid and is catalyzed with p-toluenesulfonic acid.

EXAMPLE 23 20B-Hydroxy-4-methyl-9B,l0a-pregn-4-en-3one is prepared bycondensing 20B-hydroxy-9B,l0B-desA- pregnan-S-one and ethyl vinyl ketoneaccording to the procedure of Example 5.

EXAMPLE 24 l7B-Hydroxy-5-oxo-3 ,5-seco-A-nor-andr0stan-3-oic acid isprepared by ozonolysis of testosterone according to the procedure ofExample 1.

EXAMPLE 25 17,8-Hydroxy- IOa-desA-androstan-S-one and 1 7B-hydroxy-lOB-desA-androstan-S-one are prepared froml7B-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid by conversion ofthe latter to its sodium salt followed by pyrolysis, according to theprocedure of Example 2.

EXAMPLE 26 l7B-l-lydroxy-desA-androst-9-en-5-one is prepared froml7B-hydroxy-l0a-desA-androstan-5-one by bromination followed bydehydrobromination, according to the procedure of Example 3.

EXAMPLE 26a DesA-androst-9-ene-5,l7-dione is prepared from l7-B-hydroxy-desA-androst-9-en-5-one by oxidation of the latter with a 2per cent chromic acid solution in per cent acetic acid. The so-obtaineddesA-androst- 9-ene-5,l7-dione is recrystallized from cyclohexane andmelts at l23-l23.5; [a] =+83(c 0.1021, dioxane).

EXAMPLE 27 A solution of 236 mg. of l7/3-hydroxy-desA-androst-9-en-5-one in 40 ml. per cent ethanol and 5.25 ml. 2N aqueous sodiumhydroxide solution was hydrogenated with one mole equivalent of hydrogenover 236 mg. of prereduced 5 per cent rhodium on alumina catalyst. Afterseparation of catalyst, the solution was concentrated in vacuo todryness, and the residue taken up in one liter of ether. The ethersolution was washed with water, dried over anhydrous sodium sulfate andevaporated to dryness in vacuo. From the residu 17B-hydroxy-9B,lOB-desA-androstan-S-one was obtained by crystallization. M.p. l44.5-l45; [a],; 22 (c 0.103; dioxane). The l7B-acetate (i.e.,l7fl-acetoxy- 9B,IOB-desA-androstan-S-one) is obtained by acetylation oftestosterone followed by ozonolysis, pyrolysis, bromination anddehydrobromination, and reduction according to the methods of Examples24, 25, 26 and 27 respectively, and melts at l18ll 9 [a]n 28 (c= 0.103;dioxane).

EXAMPLE 28 A solution of 238 mg. of l7B-hydr0xy-9B,l0B-desA-androstan-S-one, 1 ml. of ethylene glycol and catalytic amount ofp-toluene sulfonic acid in ml. of anhydrous benzene was slowly-distilleduntil no more water was coming over. The solution was then concentratedin vacuo to a small volume, and l7B-hydroxy-9B,1OB- desA-androstan-S-oneS-ethylene ketal was obtained from the residue by crystallization. M. p.ll5-1l6; [M -9 ((=0.0987;

dioxane).

EXAMPLE 29 To a solution of 282 mg. of l7B-hydroxy-9B,1OB-desA-androstan-S-one S-ethylene ketal in 50 ml. of methylene chloridewas added 1 equivalent of 2 per cent chromic acid in pyridine, and thereaction mixture EXAMPLE 30 To a preformed solution of one moleequivalent of prop-l '-inyl lithium in 100 ml. of anhydrous liquidammonia was added tetrahydrofuran solution of 200 mg. of 9B, 1OB-desA-androstane-S l 7-dione S-monoethylene ketal, and the reactionmixture stirred for two hours. After addition of one gram of ammoniumchloride, cooling was discontinued, and the reaction mixture allowed toevaporate. The residue was extracted with methylene chloride, theextract was washed with water, dried over anhydrous sodium sulfateandvevaporated. The residue was dissolved in 20 ml. of acetone and thecatalytic amount of p-toluenesulfonic acid added, and the solution wasrefluxed for two hours, then poured in water and extracted in methylenechloride. The methylene chloride extract was washed with water, thendried over anhydrous sodium sulfate and evaporated to dryness in vacuo.Crystallization of the residue gave l7a-(prop-l '-inyl)-l7fi-hydroxy-9,B, 10B- desA-androstan-S-one.

EXAMPLE 31 l7a-(propl -inyl l 7B-hydroxy-9/3, l Oa-androstan- 4-en-3-oneis prepared by condensing methyl vinyl ketone withl7a-(prop-l-inyl)-l7B-hydroxy-9B,1OB- desA-androstan-S-one according tothe procedure of Example 5. The product melts at l64l65.

EXAMPLE 32 To a stirred solution of one mole equivalent of 2-methylprop-Z-enyl magnesium bromide in 100 ml. of ether at roomtemperature was added dropwise asolution of 280 mg. of9B,lOB-desA-androstane-S,17-dione S-mono-ethylene ketal in 100 ml. oftetrahydrofuran. The reaction mixture was refluxed for 1 hour. Aftercooling in an ice-salt bath, a saturated solution of sodium sulfate wasslowly added to decompose the Grignard complex. This was followed byaddition of anhydrous sodium sulfate. The solution was separated byfiltration and concentrated in vacuo to dryness. The solution of theresidue and of a catalytic amount of ptoluene sulfonic acid in 20 ml. ofacetone was refluxed for two hours, then poured in water and extractedin methylene chloride. Methylene chloride extract was washed with water,dried over anhydrous sodium sulfate and evaporated to dryness. From theresidue l7a-(2'- methyl prop-2'-enyl l 7B-hydroxy-9B, l Ofi-desA-androstan-S-one was obtained.

EXAMPLE 3317a-(2'-methyl-prop-2-enyl)-17B-hydroxy-9B,l0aandrost-4-en-3-one isprepared from l7a-(2-methylprop-2 '-enyl l 7/3-hydroxy-9B, l B;desA-androstanone by condensation of the latter with methyl vinyl ketoneaccording to the procedure of Example 5. The

ethylenedioxy-desA-9B, l OB-pregnan-S-one product melts at lO6-l08.

EXAMPLE 34 l6a-Acetoxy-20-ethylenedioxy-pregn-4-en-3-one is prepared byacetylation of l6a-hydroxy-20- ethylenedioxy-pregn-4-ene-3,20-dione withone equivalent of acetic anhydride in pyridine solution at roomtemperature for 2 hours, followed by concentration to dryness in vacuo.l6a-Acetoxy-20-ethylenedioxy-5- 0xo-3,5-seco-A-norpregnan-3-oic acid isprepared by ozonolysis of l6a-acetoxy-20-ethylenedioxy-pregn-4- en-3oneaccording to the procedure of Example 1.

EXAMPLE 35 l 6a-Acetoxy-20-ethylenedioxyl Oa-desA-p re gnan- 5-one andl6a-acetoxy-20-ethylenedioxyl OB-desA- pregnan-S-one are prepared froml6a-acetoxy-20- ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis(according to the procedure of Example 2) and reacetylation with aceticanhydride and pyridine.

EXAMPLE 36 l6a-Acetoxy-ZO-ethylenedioxy-desA-pregn-9-en- 5-one isprepared from l6a-acetoxy-20-ethylenedioxy- IOa-desA-pregnan-S-one bybromination followed by dehydrobromination, according to the procedureof Example 3.

EXAMPLE 37 l6a-Acetoxy-20-ethylenedioxy-9B, l OB-desA- pregnan-S-one isprepared from l6a-acetoxy-20- ethylenedioxy-desA-pregn-9-en-5-one byhydrogenation under basic conditions in the presence of a rhodiumcatalyst, according to the procedure of Example 14.

EXAMPLE 3:;

l 601-Hydroxy-2O-ethylenedioxy-9B, 1 Oa-pregn-4-en- 3-one is prepared bycondensing l6a-acetoxy-20- with methyl vinyl ketone according to theprocedure of Example 5.

EXAMPLE 39 3B-Hydroxyl a-methyl-pregn-S-en-20-one ethylene ketal isprepared by ketalization of 3B-hydroxy-l6amethyl-pregn-S-en-ZO-one inbenzene solution with ethylene glycol using p-toluenesulfonic acid ascatalyst.

EXAMPLE 40 l6a-Methyl-20-ethylenedioxyl Oa-desA-pregnan- 5-one andl6a-methyl-20-ethylenedioxyl OB-desA- pregnan-S-one are prepared froml6a-methyl-20- ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 2.

EXAMPLE 41 16a-Methyl-ZO-ethylenedioxy-desA-pregn-9-en- -one is preparedfrom l6a-methyl-20-ethylenedioxylOa-desA-pregnan-S-one by brominationfollowed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 42 l6a-Methyl-20-ethylenedioxy-9B, l OB-desA- pregnan-S-one isprepared from l6a-methyl-20- ethylenedioxy-desA-pregn-9-en-5-one byhydrogenation under basic conditions in the presence of a rhodiumcatalyst, according to the procedure of Example 14.

EXAMPLE 43 l6a-Methyl-ZO-ethylenedioxy-9B,10a-pregn-4-en- 3-0ne isprepared by condensing l6a-methyl-20- ethylenedioxy-9B, lOB-desA-pregnan-S-one with methyl vinyl ketone, according to theprocedure of Example 5.

EXAMPLE 44 EXAMPLE 45 2 1 -Acetoxy-l la-mesoxy-20-ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of 2l-acetoxy-l la-mesoxy-20-ethylenedi0xypregn-4-en-3-one, according to theprocedure of Example ll.

EXAMPLE 46 2 l-Acetoxy-20-ethylenedioxy-desA-pregn-9-en- 5-one isprepared from 2l-acetoxy-20-ethylenedioxylla-mesoxy-3,5-seco-A-norpregnan-3-oic acid by conversion of the latterto its sodium salt followed by pyrolysis, according to the procedure ofExample 12, except that the crude product is reacetylated by treatmentwith acetic anhydride/pyridine prior to its being worked-up.

EXAMPLE 47 2 l -Acetoxy-20-ethylenedioxy-9B, l OB-desA- pregnan-S-one isprepared from 2l-acetoxy-20- ethylenedioxy-desA-pregn-9-en-5-one byhydrogena- 55 tion under acidic conditions in the presence of a rhodiumcatalyst according to the procedure of Example l5.

EXAMPLE 48 2 l -Hydroxy-20-ethylenedioxy-QB, l Oapregn-4-en- 3-one isprepared from 2l-acet0xy-20-ethylenedioxy- 9B,lOfl-desA-pregnan-S-one bycondensing the latter with methyl vinyl ketone, according to theprocedure of Example 22.

EXAMPLE 49 l la-Mesoxy-16a,l 7a-isopropylidenedioxyprogesterone isprepared by treatment of l la-hydroxy-16a,17a-isopropylidenedioxyprogesterone with methane sulfonyl chloride,according to the procedure of Example l0.

EXAMPLE 50 5 ,20-dioxo-l la-mesoxy- 1 604,17aisopropylidenedioxy-3,5-seco-A-norpregnan-3-oic acid is prepared byozonolysis of lla-mesoxy-l6a,l7aisopropylidenedioxy-progesterone,according to the procedure of Example 11.

EXAMPLE 51 16a,17a-isopropylidenedioxy-desA-pregn-9-en- 5,20-dione isprepared from 5,20-dioxo-l la-meso'xy- 16a, 17a-isopropylidenedioxy-3,5-seco-A-norpregnan- 3-oic acid by conversionof the latter to its sodium salt, followed by pyrolysis according to theprocedure of Example 12.

EXAMPLE 52 ZOa-Hydroxy- 1 611,1 7a-isopropylidenedioxy-desA-pregn-9-en-5-one is prepared from 1601,1711-isopropylidenedioxy-desA-pregn-9-ene-5,20-dione by reduction andreoxidation, according to the procedure of Example 13.

EXAMPLE 53 ZOB-Hydroxy-l601,17a-isopropylidenedioxy-9B,10B-desA-pregnan-S-one is prepared from 2OB-hydroxy- 1 601,17a-isopropylidenedioxy-desA-pregn-9-en-5-one by hydrogenation accordingto the procedure of Example l4.

EXAMPLE 54 ZOB-Hydroxy- 1 601,1 7a-isopr0pylidenedioxy-9B, lOapregn-4-en-3-one is prepared by condensing methyl vinyl ketone withZOB-hydroxy- 1 601,1 7ozisopropylidenedioxy-desA-9B, l OB-pregnan-S-oneaccording to the procedure of Example 5.

EXAMPLE 55 701,1 7a-dimethyl-l7B-hydroxy-5-oxo-3 ,S-seco-A-norandrostan-3-oic acid is prepared from 7a,l7a-di-methyl-testosteroneby ozonolysis of the latter, according to the procedure of Example 1.

EXAMPLE 56 701,1 7a-dimethyl-l 7B-hydroxy-lOa-desA-androstan- 5-one and7a,l7a-dimethyl l7B-hydroxy-lOB-desA- androstan-S-one are prepared from7a,l7a-dimethyll 7B-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 2.

EXAMPLE 5 7 701,1 7a-dimethyl-l7B-hydroxy-desA-androst-9-en- 5-one isprepared from 7a,l7a-dimethyl-l7B-hydroxy- IOa-desA-androstan-S-one bybrom-ination followed by dehydrobromination, according to the procedureof Example 3.

EXAMPLE 58 7a,l7a-dimethyl-l7B-hydroxy-desA-9B,10B- androstan-S-one isprepared from 7a,l7a-dimethyll73-hydroxy-desA-androst-9-en-5-one byhydrogena- EXAMPLE 59 701,17a-dimethyl-9B,100-testosterone is preparedfrom 7a,17a-dimethyl-l7B-hydroxy-desA-9B,10B- androstan-5-one bycondensing the latter with methyl vinyl ketone, according to theprocedure of Example 5.

EXAMPLE 60 l la-Mesoxy-l 7a-methyl-prog'esterone is prepared fromlla-hydroxy-l7a-methyl-progesterone by treatment of the latter withmethane sulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 61 l la-mesoxyl 7a-methyl-5,20-dioxo-3,5-seco-A-norpregnan-3-oicacid is prepared from lla-mesoxy-l7amethyl-progesterone by ozonolysis ofthe latter, according to the procedure of Example 1 1.

EXAMPLE 62 EXAMPLE 63 ZOB-Hydroxyl 7a-methyl-desA-pregn-9-en-5-one isprepared from l7a-methyl-desA-pregn-9-en-5,20- dione according to theprocedure of Example 13.

EXAMPLE 64 ZOB-Hydroxyl 7a-methyl-9B, l OB-desA-pregnan- S-one isprepared from l7a-methyl-20B-hydroxy-desA- pregnan-9-ene-5-one accordingto the procedure of Example l5.

EXAMPLE 65 ZOB-l-lydroxyl 7a-methyl-9B, l a-pregn-4-en-3-one is preparedby condensing l7a-methyl-2OB-hydroxy- 9B,IOB-desA-pregnan-S-one withmethyl vinyl ketone, according to the procedure of Example 4.

EXAMPLE 66 A solution of 12.8 g. of l7a-methyltestosterone in 200 ml. ofmethylene chloride and 100 ml. of ethyl acetate was ozonized for 1 hourand minutes at 70 (acetone-dry ice bath) until a blue color developed.After oxygen was bubbled through, the solution was then concentrated atroom temperature in vacuo. The residue was dissolved in 400 ml. ofacetic acid, and after addition of 30 ml. of 30 percent hydrogenperoxide, the solution was left overnight at 0. It was then evaporatedto dryness in vacuo, the residue taken up in ether, and the ethersolution extracted with 2N aqueous sodium carbonate (12 X 50 ml.). Thecombined carbonate extracts were cooled in ice, and acidified withconcentrated hydrochloric acid. The aqueous suspension of precipitatedorganic acid was extracted with methylene chloride, this extract waswashed with-water, dried over anhydrous sodium sulfate and evaporatedgiving as a colorless crystalline material 17B- hydroxyl7a-methyl-5-oxo-3 ,5-seco-A-nor-androstan- 3-oic acid. Afterrecrystallization from acetonehexane, it melted at l197, [011 9.8 (c 1.0in chloroform).

EXAMPLE 67 A solution of 10 g. of l7,8-hydroxy-l7a-methyl-5-oxo-3,5-seco-A-nor-androstan-3oic acid in 250 ml. of methanol was madealkaline to phenolphthalein with sodium ethoxide, and evaporated todryness. The residual powdery sodium salt was mixed well with 32 g. ofsodium phenylacetate and 40 g. of neutral alumina (Woelm, Grade I), andthe mixture heated at 290 in vacuo for 4 hours. After cooling to roomtemperature, a large excess of water was added, and the resultantsuspension extracted with 2 liters of ether. The ether extract waswashed with water, aqueous 2N sodium carbonate solution, and again withwater, dried and evaporated. This gave a sirupy residue, which by thinlayer chromatograms and infrared spectra consisted of l 7B-hydroxy- I7a-methyll Oa-desA-androstan-S-one asthe major andl7B-hydroxy-l7a-methyl-l0B-desA- androstan-S-one as the minor product.

Three additional pyrolyses were performed as described above, and thecombined products so-obtained was chromatographed on a 850 g. silica gelcolumn, using 5 percent ethylacetate in benzene as the eluent. Thischromotography yielded l7/3-hydroxy-l 7amethyl-lOa-desA-androstan-S-one,which after recrystallization from petroleum ether melted at 9697, [11128.2 (c 0.5 in chloroform).

Further eluates of the column gave product, 173- hydroxyl 7a-methyllOB-desA-androstan-S-one which, when recrystallized from ether, melted atl65-l67, [011 l9.8 (c 0.5 in chloroform).

To a solution of 2.2 g. of the mixture of 17B-hydroxyl7a-methyl-lOu-desA-androstan-S-one and 1 7B- hydroxyl 7a-methyllOB-desA-androstan-S-one (obtained by the above pyrolysis procedure) in50 ml. of absolute ethanol were added 20.1 ml. of a solution prepared bydissolving 2.48 g. of sodium metal in 250 ml. of absolute ethanol. Thereaction mixture was stirred overnight at room temperature. It was thenacidified with 2 ml. of glacial acetic acid, and evaporated to dryness.The residue was extracted in ether (1 liter) and the ether extractwashed with water, dried, and evaporated. The residue was crystalizedfrom petroleum ether giving a quantitative yield of17Bhydroxy-l7amethyl- 1 Ooz-desA-androstan-S-one.

EXAMPLE 68 To a solution of l 1.2 g. ofl7B-hydroxy-l7a-methyll0a-desA-androstan-5-one in 1,260 ml. of anhydrousether, stirred and cooled in anice-salt bath, were added first severaldrops of 30 percent hydrogen bromide in acetic acid, then dropwise asolution of 7.16 g. of bromine in 20 ml. of glacial acetic acid. Therate of addition of the bromine solution was synchronized with the rateof disappearance of excess bromine. After bromination was complete, 53ml. of 10 percent sodium hydrogen sulfite solution and 53 ml. of aqueous2N sodium carbonate solution were added to the reaction mixture whilestirring. The ether layer was then separated, washed with water, dried,and evaporated to dryness in vacuo. The residue was dissolved in 250 ml.of dimethylformamide, and heated with 7.5 g. of lithium carbonate at for45 minutes. After cooling, 2 liters of ether were added and the ethersolution washed with water, 1N hydrochloric acid, and then again withwa-

2. The compound of claim 11 wherein R5 is individually selected from thegroup consisting of hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy,and benzoyloxy; R5, R6 and R7 taken together are as above; and R5 and R6taken together are as above.
 3. The compound of claim 1 wherein saidcompound is a 5,20-dioxo-11 Alpha -LO-A-nor-3,5-seco-pregnan-3-oic acid.4. The compound of claim 1 wherein said compound is a 17 Alpha ,20:20,21-bismethylenedioxy-5-oxo-11 Alpha-LO-A-nor-3,5-seco-pregnan-3-oic acid.
 5. A compound as in claim 3 whichis 5,20-dioxo-11 Alpha -mesoxy-A-nor-3,5-seco-pregnan-3-oic acid.